Enhanced cardiac phosphoinositide 3-kinase (p110α) using gene therapy attenuates cardiac remodeling in type 2 diabetic mice

Abstract

Diabetic cardiomyopathy is a distinct form of heart disease that represents a major cause of death and disability in diabetic patients, particularly the more prevalent type-2 diabetic population. In the current study, we investigated administration of recombinant adeno-associated viral vectors carrying a constitutively-active PI3K(p110α) construct (rAAV6-caPI3K) at a clinically-relevant time point attenuates diabetic cardiomyopathy in a pre-clinical type-2 diabetes (T2D) model. T2D was induced by a combination of high-fat diet and low-dose streptozotocin, and confirmed by increased body weight, hyperglycemia, and impaired glucose tolerance. After 18 weeks of untreated diabetes, impaired left ventricular (LV) systolic dysfunction was evident, as confirmed by echocardiography. A single tail vein injection of rAAV6-caPI3K gene therapy was then administered. Mice were followed for an additional 8 weeks before end-point. Administration of cardiac targeted rAAV6-caPI3K attenuates diabetes-induced cardiac remodeling by limiting cardiac fibrosis and cardiomyocyte hypertrophy. The diabetes-induced LV systolic dysfunction was reversed with rAAV6-caPI3K as demonstrated by improved fractional shortening and velocity of circumferential fiber shortening. This cardioprotection occurred in combination with reduced LV ROS levels and an associated decrease in markers of endoplasmic reticulum stress. Together, the findings demonstrate that cardiac-selective increases in PI3K(p110α), via rAAV6-caPI3K, attenuates diabetic cardiomyopathy in a mouse model of T2D.